title: Upregulation of axon guidance molecules in the adult central nervous system of Nogo-A knockout mice restricts neuronal growth and regeneration.
abstract: Adult central nervous system axons show restricted growth and regeneration properties after injury. One of the underlying mechanisms is the activation of the Nogo-A/Nogo receptor (NgR1) signaling pathway. Nogo-A knockout (KO) mice show enhanced regenerative growth in vivo, even though it is less pronounced than after acute antibody-mediated neutralization of Nogo-A. Residual inhibition may involve a compensatory component. By mRNA expression profiling and immunoblots we show increased expression of several members of the Ephrin/Eph and Semaphorin/Plexin families of axon guidance molecules, e.g. EphrinA3 and EphA4, in the intact spinal cord of adult Nogo-A KO vs. wild-type (WT) mice. EphrinA3 inhibits neurite outgrowth of EphA4-positive neurons in vitro. In addition, EphrinA3 KO myelin extracts are less growth-inhibitory than WT but more than Nogo-A KO myelin extracts. EphA4 KO cortical neurons show decreased growth inhibition on Nogo-A KO myelin as compared with WT neurons, supporting increased EphA4-mediated growth inhibition in Nogo-A KO mice. Consistently, in vivo, Nogo-A/EphA4 double KO mice show increased axonal sprouting and regeneration after spinal cord injury as compared with EphA4 KO mice. Our results reveal the upregulation of developmental axon guidance cues following constitutive Nogo-A deletion, e.g. the EphrinA3/EphA4 ligand/receptor pair, and support their role in restricting neurite outgrowth in the absence of Nogo-A.
authors.affiliation: Department of Health Sciences and Technology, Brain Research Institute, University of Zurich, Swiss Federal Institute of Technology (ETH) Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
authors.forename: Anissa
authors.initials: A
authors.lastname: Kempf
authors.forename: Laura
authors.initials: L
authors.lastname: Montani
authors.forename: Marija M
authors.initials: MM
authors.lastname: Petrinovic
authors.forename: Aileen
authors.initials: A
authors.lastname: Schroeter
authors.forename: Oliver
authors.initials: O
authors.lastname: Weinmann
authors.forename: Andrea
authors.initials: A
authors.lastname: Patrignani
authors.forename: Martin E
authors.initials: ME
authors.lastname: Schwab
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D036384:Ephrin-A3 / Q000235:genetics / Q000378:metabolism; D036385:Ephrin-A4 / Q000235:genetics / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism; D000070798:Nogo Proteins; D011712:Pyramidal Tracts / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000378:metabolism; D058630:Spinal Cord Regeneration; D015854:Up-Regulation
chemical_list: D036384:Ephrin-A3; D036385:Ephrin-A4; D009185:Myelin Proteins; D000070798:Nogo Proteins; D012333:RNA, Messenger; C000603201:Rtn4 protein, mouse
keywords: EphA4; EphrinA3; Nogo-A; compensation; myelin; spinal cord injury